Glaucoma is an ocular disorder most often characterized by increased intraocular pressure which, over time, may cause impaired vision or blindness. Treatment may involve topical agents such as pilocarpine (a cholinomimetic drug); timolol (a Beta-adrenergic blocking agent); epinephrine (an alpha and beta adrenergic receptor antagonist); dipevefrin (a prodrug of epinephrine) and demecarium bromide (a cholinesterase inhibitor). Systemic agents used to treat glaucoma include carbonic anhydrase inhibitors such as acetazolamide.
Ketanserin, a systemic anti-hypertensive agent, is an antagonist of the actions of serotonin (5-HT) that has been characterized as highly specific for S.sub.2 (5-HT.sub.2) receptors. Ketanserinol is the main metabolite of ketanserin. Ketanserin is disclosed in U.S. Pat. No. 4,335,127 as an anticongestive. The ketanserinol metabolite is obtained by enzymatic reduction of ketanserin in biological systems according to the following reaction: ##STR1## W. Meuldermans, J. Hendrick, W. Lauwers, E. Swysen, R. Hurkmans, F. Knaeps, R. Woestenborghs, J. Heykants, "Excretion and Biotransformation of Ketanserin after Oral and Intravenous Administration in Rats and Dogs", Drug Metab. Dispos., (1984) 12:772-781 and W. Meuldermans, et al., Arch. Int. Pharmacodyn, (1985) 274:330, disclose methods for carrying out this reaction. The entire disclosure of both of these references are hereby incorporated herein by reference.
Systemically, ketanserin is enzymatically reduced to ketanserinol and excreted in the urine and feces and is approximately 1000 times less active as an anti-hypertensive agent than ketanserin. Ketanserin is also reduced to ketanserinol in the eye.
Intraocular Pressure (IOP) effects have been previously investigated for ketanserin see, F. W. Change et al. "Mechanism of the Ocular Hypotensive Action of Ketanserin," J. Ocular Pharmacol., 1(2):137-147 (1985); C. Costagliola et al., "Effect of Oral Ketanserin Administration on Intraocular Pressure in Glaucomatous Patients", Exp. Eye Res. (1991), 52, 507-510; and M. Cellini, A. Baldi, R. Caramazza "Ketanserin and Intraocular Pressure: A Preliminary Study", New Trends in Ophthalmology, Vol. VI, No. 2/1991 127-130 (1991), however, ketanserinol intraocular pressure effects have not been studied.
It is an object of the present invention to provide an agent for reducing the effects of intraocular pressure on the eye and to provide a treatment for glaucoma. It has been found by the present inventors that the ocular activity of ketanserinol on IOP is far superior to that of ketanserin and is comparable to commercially existing anti-glaucoma products.
It is a further object of the present invention to use ketanserinol as an effective agent for treatment of glaucoma by lowering intraocular pressure.